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An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
08:43

An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment

Published on: July 28, 2012

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

Shaguna Seth1, Yoshiyuki Matsui, Kathy Fosnaugh

  • 1Discovery Research and Pharmaceutical Development, Marina Biotech Inc., Bothell, Washington 98021, USA. sseth@marinabio.com

Molecular Therapy : the Journal of the American Society of Gene Therapy
|March 3, 2011
PubMed

Insights

New unlocked nucleobase analog siRNA (UsiRNA) delivered via liposomes effectively silenced survivin and PLK1 genes in a bladder cancer model, reducing tumor volume. This RNA interference therapy shows promise for bladder cancer treatment.

Area of Science:

  • * Molecular Biology
  • * Cancer Therapeutics
  • * Nanotechnology

Background:

  • * RNA interference (RNAi) offers a novel strategy for cancer therapy by silencing aberrant gene expression.
  • * Developing effective short interfering RNA (siRNA) and delivery systems is crucial for targeted gene silencing.
  • * Survivin and polo-like kinase-1 (PLK1) are key genes implicated in bladder cancer progression.

Purpose of the Study:

  • * To develop and evaluate novel siRNA constructs (UsiRNA) targeting survivin and PLK1 genes for bladder cancer therapy.
  • * To assess the efficacy of UsiRNA encapsulated in a novel liposome delivery system (DiLA(2)) for intravesical administration.
  • * To confirm the mechanism of gene silencing and its impact on tumor growth in a preclinical model.

Main Methods:

  • * Design and synthesis of unlocked nucleobase analog siRNA (UsiRNA) targeting survivin and PLK1.
  • * Encapsulation of UsiRNA into specifically formulated dialkylated amino acid-based liposomes (DiLA(2)).
  • * Evaluation of intravesical DiLA(2)-UsiRNA treatment in an orthotopic bladder cancer mouse model, assessing mRNA inhibition, tumor volume, and mechanism of action.

Main Results:

  • * Intravesical administration of UsiRNA targeting survivin or PLK1 in DiLA(2) liposomes achieved significant mRNA inhibition (90% and 70%, respectively).
  • * Treatment resulted in a dose-dependent and sustained reduction in bladder tumor volumes over a 3-week period.
  • * Gene silencing was confirmed to be mediated by the RNA-induced silencing complex (RISC), with detectable cleavage products in tumors.

Conclusions:

  • * Survivin or PLK1 UsiRNA delivered via DiLA(2) liposomes demonstrate potent therapeutic potential for bladder cancer.
  • * Intravesical instillation of these UsiRNAs represents a promising RNA interference-based treatment strategy.
  • * The developed UsiRNA and DiLA(2) delivery system offer a viable approach for targeted cancer gene therapy.

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