title: 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.affiliation: Discovery Research and Pharmaceutical Development, Marina Biotech Inc., Bothell, Washington 98021, USA. sseth@marinabio.com
authors.forename: Shaguna
authors.initials: S
authors.lastname: Seth
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsui
authors.forename: Kathy
authors.initials: K
authors.lastname: Fosnaugh
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Narendra
authors.initials: N
authors.lastname: Vaish
authors.forename: Roger
authors.initials: R
authors.lastname: Adami
authors.forename: Pierrot
authors.initials: P
authors.lastname: Harvie
authors.forename: Rachel
authors.initials: R
authors.lastname: Johns
authors.forename: Gregory
authors.initials: G
authors.lastname: Severson
authors.forename: Tod
authors.initials: T
authors.lastname: Brown
authors.forename: Akihide
authors.initials: A
authors.lastname: Takagi
authors.forename: Susan
authors.initials: S
authors.lastname: Bell
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Tianying
authors.initials: T
authors.lastname: Zhu
authors.forename: Renata
authors.initials: R
authors.lastname: Fam
authors.forename: Iwona
authors.initials: I
authors.lastname: Maciagiewicz
authors.forename: Erin
authors.initials: E
authors.lastname: Kwang
authors.forename: Michael
authors.initials: M
authors.lastname: McCutcheon
authors.forename: Ken
authors.initials: K
authors.lastname: Farber
authors.forename: Patrick
authors.initials: P
authors.lastname: Charmley
authors.forename: Michael E
authors.initials: ME
authors.lastname: Houston
authors.forename: Alan
authors.initials: A
authors.lastname: So
authors.forename: Michael V
authors.initials: MV
authors.lastname: Templin
authors.forename: Barry
authors.initials: B
authors.lastname: Polisky
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000008:administration & dosage; D002788:Cholesterol Esters / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D010714:Phosphatidylethanolamines / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics*; D000077022:Survivin; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D002784:Cholesterol; D002788:Cholesterol Esters; D051034:Inhibitor of Apoptosis Proteins; D008081:Liposomes; D010714:Phosphatidylethanolamines; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D000097869:Polo-Like Kinase 1; C117749:Birc5 protein, mouse; C013440:cholesteryl succinate; C018525:1,2-dimyristoylphosphatidylethanolamine