Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers

Aliaksei Ihnatsyeu-Kachan (1) , Volha Dzmitruk (1) , Evgeny Apartsin (2) , Olga Krasheninina (2) , Maksim Ionov (3) , Svetlana Loznikova (1) , Alya Venyaminova (2) , Katarzyna Miłowska (3) , Dzmitry Shcharbin (1) , Serge Mignani (4, 5) , Maria Angeles Muñoz-Fernàndez (6, 7) , Jean Pierre Majoral (8) , Maria Bryszewska (3)

1 Institute of Biophysics and Cell Engineering, NASB, Minsk
2 ICBFM SB RAS - Institute of Chemical Biology and Fundamental Medicine [Novosibirsk, Russia]
3 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz
4 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
5 Centro de Química da Madeira
6 CIBER-BBN - Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine
7 Laboratorio de Inmuno-Biología Molecular
8 LCC - Laboratoire de chimie de coordination

Currently, RNAi based approaches for cancer treatment involving short double stranded RNA molecules (siRNA) are under vigorous scrutinization. Due to numerous biological obstacles, siRNA delivery into target cells requires protective escort. On the other hand, combining of siRNA-mediated gene silencing and action of conventional chemotherapeutics can propose additional enhancement of anticancer activity. In the present study, we investigated a siRNA cocktail able to downregulate anti-apoptotic genes (BCL-xL, BCL-2, MCL-1) and the chemotherapeutic agent 5-fluorouracil (5-FU) to evaluate multi-target cytotoxic effect on human cervical carcinoma cells (HeLa cell line). Novel phosphorus containing dendrimers of 3rd and 4th generations (namely AE2G3 and AE2G4) with voluminous piperidine terminal cationic groups were designed and tested as siRNA carriers. Dendrimers of both generations showed remarkable ability to bind pro-apoptotic siRNAs and provided 80–100% siRNA uptake by HeLa cells in the serum containing medium, while the widespread transfection agent Lipofectamine showed only ~40% uptake. SiRNA cocktail (in low concentrations 50 and 100 nM) delivered by AE2G3 dendrimer caused almost complete elimination of cancer cells. We have discovered considerable increase of 5-FU cytotoxic effect by addition of AE2G3/siRNA cocktail complexes in low doses. Thus, we demonstrated the effectiveness of combined multi-target siRNA anticancer approach and described new highly effective serum stable nanomaterial vehicle for gene-based drugs.

Mots clés: Phosphorus dendrimers; siRNA; 5-fluorouracil; Cancer; Combination therapy

Domaines: Chimie de coordination

Aliaksei Ihnatsyeu-Kachan, Volha Dzmitruk, Evgeny Apartsin, Olga Krasheninina, Maksim Ionov, et al.. Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers. Colloids and Interfaces, 2018, 1 (1), pp.6. ⟨10.3390/colloids1010006⟩. ⟨hal-02336640⟩