RNAi-based Therapeutics Targeting Survivin and PLK1 for Treatment of Bladder Cancer
Autor: | Yan Chen, Erin Kwang, Rachel E. Johns, Renata Fam, Michael McCutcheon, Feng Chen, Alan So, Gregory Severson, Barry Polisky, Michael V. Templin, Yoshiyuki Matsui, Roger C. Adami, Tod Brown, Kathy Fosnaugh, Iwona M. Maciagiewicz, Pierrot Harvie, Yan Liu, Shaguna Seth, Akihide Takagi, Narendra K. Vaish, Tianying Zhu, Susan Bell, Ken Farber, Michael E. Houston, Patrick Charmley |
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Rok vydání: | 2011 |
Předmět: |
Small interfering RNA
Survivin Blotting Western Gene Expression Mice Nude Cell Cycle Proteins Biology Protein Serine-Threonine Kinases Polymerase Chain Reaction Inhibitor of Apoptosis Proteins Mice RNA interference Cell Line Tumor Proto-Oncogene Proteins Gene expression Drug Discovery medicine Genetics Gene silencing Animals Humans RNA Messenger RNA Small Interfering Molecular Biology Pharmacology Messenger RNA Bladder cancer Phosphatidylethanolamines RNA medicine.disease Repressor Proteins Disease Models Animal Administration Intravesical Cholesterol Urinary Bladder Neoplasms Liposomes Cancer research Molecular Medicine Female RNA Interference Original Article Cholesterol Esters |
Zdroj: | Molecular Therapy. 19(5):928-935 |
ISSN: | 1525-0016 |
DOI: | 10.1038/mt.2011.21 |
Popis: | 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. |
Databáze: | OpenAIRE |
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