Camptothecin prodrug based on cationic amino acid modification, preparation method thereof, nano drug-loaded particles and application thereof

A cationic amino acid, camptothecin technology, which is applied in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc. problem, to achieve the effect of good killing effect and excellent stability

Active Publication Date: 2019-01-11
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, camptothecin itself has many disadvantages, such as insoluble in water, unstable lactone ring, etc., which seriously affect its efficacy [see Yan Gao, Lingbing Li, Guangxi Zhai. Preparation and characterization of Pluronic / TPGS mixed micelles for solubilization of camptothecin.Colloids and Surfaces B:Biointerfaces.2008, 64,194-199; Julianne Fassberg,Valentino J.Stella.A kinetic and mechanical study of the hydrolysis of camptothecin and someanalogues.J.Pharm.Sci.,1992,81,676- 684]
In addition, not only is camptothecin itself poor in water solubility, but it is also difficult to load it by common methods.

Method used

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  • Camptothecin prodrug based on cationic amino acid modification, preparation method thereof, nano drug-loaded particles and application thereof
  • Camptothecin prodrug based on cationic amino acid modification, preparation method thereof, nano drug-loaded particles and application thereof
  • Camptothecin prodrug based on cationic amino acid modification, preparation method thereof, nano drug-loaded particles and application thereof

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preparation example Construction

[0023] The present invention provides a kind of preparation method of the camptothecin prodrug based on cationic amino acid modification described in above-mentioned technical scheme, comprises the following steps:

[0024] Condensation reaction of camptothecin and group-protected amino acid in the presence of condensing agent and solvent, deprotection, to obtain camptothecin prodrug based on cationic amino acid modification, having formula I, formula II, formula III, formula IV or Formula V structure;

[0025] The amino acid protected by the group is selected from bis-tert-butoxycarbonyl protected lysine, tert-butoxycarbonyl and 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl Protected arginine, bis-tert-butoxycarbonyl-protected histidine, bis-tert-butoxycarbonyl-protected tryptophan or tert-butoxycarbonyl-protected proline.

[0026] The present invention preferably carries out the condensation reaction under anhydrous conditions. In the present invention, the temperatur...

Embodiment 1

[0045] Preparation of Cationic Amino Acid Modified Camptothecin Prodrug

[0046] (1) Under anhydrous conditions, combine camptothecin (CPT) with bis-tert-butoxycarbonyl-protected lysine (Boc-Lys(Boc)-OH), tert-butoxycarbonyl, 2,2,4 , 6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl protected arginine (Boc-Arg(Pbf)-OH), bis-tert-butoxycarbonyl protected histidine (Boc-His (Boc)-OH), bis-tert-butoxycarbonyl-protected tryptophan (Boc-Trp(Boc)-OH) and tert-butoxycarbonyl-protected proline Pro(Boc)-OH)) according to the molar ratio of 1 : 1.2 Disperse in a certain volume of dichloromethane, and add 4-dimethylaminopyridine (DMAP) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt of 2 times the amount of amino acid Condensation reaction of hydrochloric acid (EDC HCl) at room temperature, the reaction time is 2 days, then remove dichloromethane, add trifluoroacetic acid, deprotect, and settle in 10 times the volume of ether, the obtained solid is amino acid Modified camptothecin pr...

Embodiment 2

[0054] Embodiment 2: the drug loading capacity of the modified camptothecin of cationic amino acid

[0055] CPTK, CPTR, CPTH, CPTW, and CPTP provided by the present invention can be electrostatically compounded with PLG to obtain higher drug loading efficiency (drug loading %=loaded CPT mass / (loaded CPT mass+carrier mass)*100 %). CPTK / PLG, CPTR / PLG, CPTH / PLG, CPTW / PLG, and CPTP / PLG. Its preparation and detection methods are as follows:

[0056] Prepare a certain concentration of CPTK, CPTR, CPTH, CPTW, CPTP aqueous solution (solution X), the concentration of which is 5 mg / mL. and an aqueous solution of PLG at a concentration of 5 mg / mL (solution Y). Take certain mentioned X solution and Y solution and mix them according to different mass ratios, such as X / Y=1 / 1, 1 / 2, 1 / 4, and vortex evenly to form nanoparticles. Each complex solution was dialyzed against acidic water (pH=5) with a 3500Da dialysis bag for 24 hours, the solution in the dialysis bag was taken out, after freez...

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Abstract

The invention provides a camptothecin prodrug based on cationic amino acid modification, a preparation method thereof, nano drug-loaded particles and an application thereof. The camptothecin prodrug has the structure of formula I, formula II, formula III, formula IV or formula V; the prodrug of camptothecin with the above structure is a water-soluble chemotherapeutic agent, and has excellent stability. Camptothecin has anticancer activity similar to that of camptothecin itself. The prodrug of camptothecin has a positive charge and can be electrostatically combined with a negatively charged polymer in situ to obtain nano-drug-loaded particles with uniform nano-particle size and small particle size, and has high drug-loading capacity. The drug-loaded nanoparticles have good killing effect onMCF7, CT26, 4T1, HeLa, A549 and other tumor cells. After storage in PBS for 2 days, the lactone ring will not change into carboxylate form and lose its pharmacodynamics. The particle size of drug-loaded nanoparticles ranged from 45 nm to 55 nm. The drug loading of nanoparticles is 23 - 48.5%.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, and in particular relates to a cationic amino acid-modified camptothecin prodrug, a preparation method thereof, nano drug-loaded particles and an application thereof. Background technique [0002] Therapies such as radiotherapy, chemotherapy, genetics, immunity and surgery have become the main means of cancer treatment. Chemotherapy, as a traditional cancer treatment method, still has extensive research. Common broad-spectrum anticancer drugs include doxorubicin, paclitaxel and camptothecin, etc., which have good killing effects on most cancer cells and are widely used in clinical research. However, most anticancer drugs have poor water solubility and low utilization rate, resulting in poor antitumor effect when applied in vivo. Therefore, researchers use various methods to improve their solubility in water, so as to improve the effect of their application in vivo. [0003] Campto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K47/34A61K47/36A61K31/4745A61P35/00
CPCA61K9/146A61K31/4745A61P35/00C07D491/22
Inventor 田华雨郭兆培陈学思林琳陈杰孙平杰
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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