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

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Institute of Biophysics and Cell Engineering of NASB, 220072 Minsk, Belarus
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Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk 630090, Russia
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Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
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Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, PRES Sorbonne Paris Cité, CNRS UMR 8601, 75006 Paris, France
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Centro de Química da Madeira, MMRG, Universidade da Madeira, 9000-390 Funchal, Portugal
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Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain
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Laboratorio de Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
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Laboratoire de Chimie de Coordination du CNRS, 31077 Toulouse CEDEX 4, France
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Université de Toulouse, UPS, INP, 31077 Toulouse CEDEX 4, France
*
Author to whom correspondence should be addressed.
Colloids Interfaces 2017, 1(1), 6; https://doi.org/10.3390/colloids1010006
Received: 9 October 2017 / Revised: 27 October 2017 / Accepted: 10 November 2017 / Published: 13 November 2017
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. View Full-Text
Keywords: phosphorus dendrimers; siRNA; 5-fluorouracil; cancer; combination therapy phosphorus dendrimers; siRNA; 5-fluorouracil; cancer; combination therapy
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Ihnatsyeu-Kachan, A.; Dzmitruk, V.; Apartsin, E.; Krasheninina, O.; Ionov, M.; Loznikova, S.; Venyaminova, A.; Miłowska, K.; Shcharbin, D.; Mignani, S.; Muñoz-Fernández, M.A.; Majoral, J.-P.; Bryszewska, M. Multi-Target Inhibition of Cancer Cell Growth by SiRNA Cocktails and 5-Fluorouracil Using Effective Piperidine-Terminated Phosphorus Dendrimers. Colloids Interfaces 2017, 1, 6.

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