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Nucleic Acids Research Advance Access published online on May 29, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp451
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth

Laurence Crombez1, May Catherine Morris1, Sandrine Dufort2,3, Gudrun Aldrian-Herrada1, Quan Nguyen4, Gary Mc Master4, Jean-Luc Coll2,3, Frederic Heitz1 and Gilles Divita1,*

1Centre de Recherches de Biochimie Macromoléculaire, Department of Molecular Biophysics and Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, 34293 Montpellier, 2INSERM CRI U823, Institut Albert Bonniot, Grenoble Cedex 9, 3University Joseph Fourier, Grenoble, France and 4Panomics Inc., 6519 Dumbarton Circle Fremont, CA 94555, USA

*To whom correspondence should be addressed. Tel: +33 (0)4 67 61 33 92; Fax: +33 (0)4 67 52 15 59; Email: gilles.divita{at}crbm.cnrs.fr

Received May 12, 2009. Revised May 12, 2009. Accepted May 13, 2009.

The development of short interfering RNA (siRNA), has provided great hope for therapeutic targeting of specific genes responsible for patholological disorders. However, the poor cellular uptake and bioavailability of siRNA remain a major obstacle to their clinical development and most strategies that propose to improve siRNA delivery remain limited for in vivo applications. In this study, we report a novel peptide-based approach, MPG-8 an improved variant of the amphipathic peptide carrier MPG, that forms nanoparticles with siRNA and promotes their efficient delivery into primary cell lines and in vivo upon intra-tumoral injection. Moreover, we show that functionalization of this carrier with cholesterol significantly improves tissue distribution and stability of siRNA in vivo, thereby enhancing the efficiency of this technology for systemic administration following intravenous injection without triggering any non-specific inflammatory response. We have validated the therapeutic potential of this strategy for cancer treatment by targeting cyclin B1 in mouse tumour models, and demonstrate that tumour growth is compromised. The robustness of the biological response achieved through this approach, infers that MPG 8-based technology holds a strong promise for therapeutic administration of siRNA.


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