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

• Published in: Nucleic acids research 2009-08, Vol.37 (14), p.4559-4569
• Main Authors: Crombez, Laurence, Morris, May Catherine, Dufort, Sandrine, Aldrian-Herrada, Gudrun, Nguyen, Quan, Mc Master, Gary, Coll, Jean-Luc, Heitz, Frederic, Divita, Gilles
• Format: Article
• Language: English
• Subjects: Animals; Biochemistry, Molecular Biology; Cell Line, Tumor; Cell Proliferation; Cyclin B; Cyclin B - antagonists & inhibitors; Cyclin B - genetics; Cyclin B1; Female; G2 Phase; Humans; Injections; Life Sciences; Mice; Mice, Nude; Nanoparticles; Nanoparticles - chemistry; Neoplasms; Neoplasms - pathology; Neoplasms - therapy; Oligopeptides; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; Peptides; Peptides - chemistry; RNA; RNA, Small Interfering; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - pharmacokinetics; RNA-Binding Proteins; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - pharmacokinetics
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkp451

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.