RNAi-based therapeutics targeting survivin and PLK1 for treatment of bladder cancer.

Abstract

Harnessing RNA interference (RNAi) to silence aberrant gene expression is an emerging approach in cancer therapy. Selective inhibition of an overexpressed gene via RNAi requires a highly efficacious, target-specific short interfering RNA (siRNA) and a safe and efficient delivery system. We have developed siRNA constructs (UsiRNA) that contain unlocked nucleobase analogs (UNA) targeting survivin and polo-like kinase-1 (PLK1) genes. UsiRNAs were encapsulated into dialkylated amino acid-based liposomes (DiLA(2)) containing a nor-arginine head group, cholesteryl hemisuccinate (CHEMS), cholesterol and 1, 2-dimyristoyl-phosphatidylethanolamine-polyethyleneglycol 2000 (DMPE-PEG2000). In an orthotopic bladder cancer mouse model, intravesical treatment with survivin or PLK1 UsiRNA in DiLA(2) liposomes at 1.0 and 0.5 mg/kg resulted in 90% and 70% inhibition of survivin or PLK1 mRNA, respectively. This correlated with a dose-dependent decrease in tumor volumes which was sustained over a 3-week period. Silencing of survivin and PLK1 mRNA was confirmed to be RNA-induced silencing complex mediated as specific cleavage products were detected in bladder tumors over the duration of the study. This report suggests that intravesical instillation of survivin or PLK1 UsiRNA can serve as a potential therapeutic modality for treatment of bladder cancer.

• Authors: Shaguna Seth, Yoshiyuki Matsui, Kathy Fosnaugh, Yan Liu, Narendra Vaish, Roger Adami, Pierrot Harvie, Rachel Johns, Gregory Severson, Tod Brown, Akihide Takagi, Susan Bell, Yan Chen, Feng Chen, Tianying Zhu, Renata Fam, Iwona Maciagiewicz, Erin Kwang, Michael McCutcheon, Ken Farber, Patrick Charmley, Michael E Houston Jr, Alan So, Michael V Templin, Barry Polisky
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 5 Pg. 928-35 (May 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21364537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Birc5 protein, mouse
• Cell Cycle Proteins
• Cholesterol Esters
• Inhibitor of Apoptosis Proteins
• Liposomes
• Phosphatidylethanolamines
• Proto-Oncogene Proteins
• RNA, Messenger
• RNA, Small Interfering
• Repressor Proteins
• Survivin
• Cholesterol
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• cholesteryl succinate
• 1,2-dimyristoylphosphatidylethanolamine

Topics

• Administration, Intravesical
• Animals
• Blotting, Western
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cholesterol (administration & dosage)
• Cholesterol Esters (administration & dosage)
• Disease Models, Animal
• Female
• Gene Expression
• Humans
• Inhibitor of Apoptosis Proteins (genetics)
• Liposomes (administration & dosage)
• Mice
• Mice, Nude
• Phosphatidylethanolamines (administration & dosage)
• Polymerase Chain Reaction
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA Interference
• RNA, Messenger (genetics)
• RNA, Small Interfering (administration & dosage, genetics, therapeutic use)
• Repressor Proteins (genetics)
• Survivin
• Urinary Bladder Neoplasms (genetics, pathology, therapy)