Targeting cyclin B1 through peptide-based delivery of siRNA prevents tumour growth.
The development of short interfering RNA (siRNA), has provided great hope for therapeutic targeting of specific genes responsible for pathological 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.
Crombez
Laurence
L
Centre de Recherches de Biochimie Macromoléculaire, Department of Molecular Biophysics and Therapeutic, UMR-5237 CNRS-UM2-UM1, 1919 Route de Mende, 34293 Montpellier, France.
Morris
May Catherine
MC
Dufort
Sandrine
S
Aldrian-Herrada
Gudrun
G
Nguyen
Quan
Q
Mc Master
Gary
G
Coll
Jean-Luc
JL
Heitz
Frederic
F
Divita
Gilles
G
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019926:Cyclin B / Q000037:antagonists & inhibitors* / Q000235:genetics; D056744:Cyclin B1; D005260:Female; D016195:G2 Phase; D006801:Humans; D007267:Injections; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D010455:Peptides / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000493:pharmacokinetics
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; C543105:MPG-8 peptide; D009842:Oligopeptides; D010455:Peptides; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins