Antitumor efficiency of the natural alkaloid berberine complexed with C60fullerene in Lewis lung carcinoma in vitro and in vivo

Autor: Grebinyk, Anna, Prylutska, Svitlana, Grebinyk, Sergii, Evstigneev, Maxim, Krysiuk, Iryna, Skaterna, Tetiana, Horak, Iryna, Sun, Yanfang, Drobot, Liudmyla, Matyshevska, Olga, Prylutskyy, Yuriy, Ritter, Uwe, Frohme, Marcus
Zdroj: Cancer Nanotechnology; December 2021, Vol. 12 Issue: 1
Abstrakt: Background: Berberine (Ber) is a herbal alkaloid with pharmacological activity in general and a high anticancer potency in particular. However, due to its low bioavailability, the difficulty in reaching a target and choosing the right dose, there is a need to improve approaches of Ber use in anticancer therapy. In this study, Ber, noncovalently bound to a carbon nanostructure C60fullerene (C60) at various molar ratios of the components, was explored against Lewis lung carcinoma (LLC). Methods: C60–Ber noncovalent nanocomplexes were synthesized in 1:2, 1:1 and 2:1 molar ratios. Ber release from the nanocomplexes was studied after prolonged incubation at different pH with the liquid chromatography–mass spectrometry analysis of free Ber content. Biological effects of the free and C60-complaxated Ber were studied in vitro towards LLC cells with phase-contrast and fluorescence microscopy, flow cytometry, MTT reduction, caspase activity and wound closure assays. The treatment with C60–Ber nanocomplex was evaluated in vivo with the LLC-tumored C57Bl mice. The mice body weight, tumor size, tumor weight and tumor weight index were assessed for four groups, treated with saline, 15 mg C60/kg, 7.5 mg Ber/kg or 2:1 C60-Ber nanocomplex (15 mg C60/kg, 7.5 mg Ber/kg). Results: Ber release from C60–Ber nanocomplexes was promoted with medium acidification. LLC cells treatment with C60–Ber nanocomplexes was followed by enhanced Ber intracellular uptake as compared to free Ber. The cytotoxicity of the studied agents followed the order: free Ber < 1:2 < 1:1 < 2:1 C60–Ber nanocomplex. The potency of cytotoxic effect of 2:1 C60–Ber nanocomplex was confirmed by 21.3-fold decrease of IC50value (0.8 ± 0.3 µM) compared to IC50for free Ber (17 ± 2 µM). C60–Ber nanocomplexes induced caspase 3/7 activation and suppressed the migration activity of LLC cells. The therapeutic potency of 2:1 C60–Ber nanocomplex was confirmed in a mouse model of LLC. The tumor growth in the group treated with 2:1 C60–Ber nanocomplex is suppressed by approximately 50% at the end of experiment, while in the tumor-bearing group treated with free Ber no therapeutic effect was detected. Conclusions: This study indicates that complexation of natural alkaloid Ber with C60may be a novel therapeutic strategy against lung carcinoma. Graphical abstract:
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