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Capsicine-camptothecin anti-cancer drug conjugate and preparation method and application thereof

An anticancer drug, capsaicin technology, applied in the directions of drug combinations, antitumor drugs, pharmaceutical formulations, etc., to achieve the effects of high yield, good safety, and simple preparation method

Inactive Publication Date: 2015-03-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] There is no report on the combined use of capsaicin and camptothecin anticancer drugs

Method used

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  • Capsicine-camptothecin anti-cancer drug conjugate and preparation method and application thereof
  • Capsicine-camptothecin anti-cancer drug conjugate and preparation method and application thereof
  • Capsicine-camptothecin anti-cancer drug conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of embodiment 1 capsaicin-SN-38 conjugate (C10 hydroxyl)

[0040] The preparation method of a kind of capsaicin-SN-38 conjugate of this embodiment (synthetic route sees figure 1 ), including the following steps:

[0041] (1) Synthesis of capsaicin derivative 3

[0042] Dissolve capsaicin (658mg, 2mmol) and DMAP (289mg, 2.4mmol) in 1ml of pyridine, add succinic anhydride (517.4mg, 5mmol), react at 40°C for 4h, remove the reaction solvent; the residual solid is dissolved in dichloromethane , and then washed with 5% citric acid and saturated brine respectively; the organic phase was dried over anhydrous sodium sulfate, and after filtration, the filtrate was collected and the solvent was removed under reduced pressure; the solid was separated and purified by column chromatography (dichloromethane:methanol=100 : 1) obtain capsaicin derivative 3 after.

[0043] capsaicin derivative 3 1 The H NMR nuclear magnetic data is as follows:

[0044] 1 H NMR (400M...

Embodiment 2

[0048] Embodiment 2 Preparation of capsaicin-SN-38 conjugate self-emulsifying particles

[0049] The conjugate 1 (20 mg) of Example 1 was dissolved in 1 mL Tween 80 solution to obtain a self-emulsifying preparation, and then the self-emulsifying preparation was slowly injected into water (final concentration 2 mg / mL), and gently shaken and vibrated to form nanoparticles.

[0050] Take a small amount of the above-prepared nanoparticle solution, spot it on a copper grid, negatively stain it with 2% uranyl acetate, and observe it with a transmission film. Depend on figure 2 It can be seen that the self-emulsifying preparation forms milk particles of relatively uniform size after being diluted with water.

Embodiment 3

[0051] Example 3 In vitro cytotoxicity evaluation

[0052] In order to evaluate the killing ability of the conjugate 1 self-emulsified particles obtained in Example 2 on tumor cells, taking intestinal cancer cells HCT-116 and SW480, lung cancer cells H1299 and breast cancer cells MDA-MB-231 and MCF-7 as examples, The drug efficacy was evaluated by MTT method, and the IC of the drug on different cells was investigated. 50 Value (drug concentration at the time of inducing tumor cell apoptosis by 50%), with CPT-11, capsaicin and SN-38 as controls. The evaluation results are shown in Table 1.

[0053] Table 1 In vitro cytotoxicity evaluation results of each test drug

[0054]

[0055] As can be seen from Table 1, after 48 hours of co-cultivation of the self-emulsifying particles of the conjugate 1 and the cells, the results showed that the IC of the conjugate 1 on SW480 cells 50 0.07±0.03μM, its in vitro anti-tumor activity is 408 times that of CPT-11, 3 times that of SN-38;...

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Abstract

The invention discloses a capsicine-camptothecin anti-cancer drug conjugate and a preparation method and application thereof. In the preparation method disclosed by the invention, chemical modification is performed on capsicine, the modified capsicine is coupled to camptothecin anti-cancer drug through ester bonds, and the obtained capsicine-camptothecin anti-cancer drug conjugate can be dissolved in pharmacy solvents which can be accepted in clinic, for example, Tween, so that the conjugate can be directly used for oral medication in clinic; coupling occurs on C20 hydroxy of the camptothecin or on C10 or C20 hydroxy of SN-38. Through the coupling of the ester bonds, the conjugate can directly release two kinds of activated components in a body in a hydrolytic manner. On one hand, the camptothecin or the SN-38 can be released without the catalytic hydrolysis of carboxylesterase, so that the bioavailability of the SN-38 can be effectively improved; on the other hand, the capsicine has a certain anti-cancer activity and can take synergistic action with the SN-38 after being released in the body, so that the anti-cancer effect of the SN-38 is intensified.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a capsaicin-camptothecin anticancer drug conjugate and a preparation method and application thereof. Background technique [0002] Camptothecin (CPT) is an indole alkaloid isolated from Chinese involucrata plants, which can specifically inhibit DNA topoisomerase I, leading to cell death, thereby producing anti-tumor effects. However, camptothecin anticancer drugs are insoluble in water, which limits their clinical application. The solubility of drugs can be increased by modifying them with suitable hydrophilic groups. [0003] Currently, camptothecin anticancer drugs approved for clinical application include irinotecan (Irinotecan, CPT-11) and topotecan (Topotecan). Among them, irinotecan is hydrolyzed by carboxylesterase in the liver and tumor tissue to generate SN-38 (7-ethyl-10-hydroxycamptothecin) with strong anti-tumor activity, but the conversion effi...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61P35/00
CPCC07D491/22
Inventor 王杭祥徐骁陈建美吴佳萍耿磊谢海洋周琳郑树森
Owner ZHEJIANG UNIV
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