Tailoring nanostructured solid-lipid carriers for time-controlled intracellular siRNA kinetics to sustain RNAi-mediated chemosensitization

Biomaterials. 2011 Apr;32(10):2662-72. doi: 10.1016/j.biomaterials.2010.12.029. Epub 2011 Jan 14.

Abstract

Use of siRNA for silencing major oncogenic/chemoresistance targets such as survivin has strong potential for cancer therapy. However, a key clinical limitation is their short action, preventing them from sustaining their therapeutic RNA-interference activity for optimal chemosensitization. This issue is tackled from the perspective of intracellular siRNA kinetics using a novel lipid-based "nanostructured siRNA carrier" (NSC), which incorporates variable amount of oil phase into the solid-lipid matrix to modify its siRNA release behaviors. We demonstrate that by manipulating the degradation responses of NSC device to lysosomal enzyme, tailoring of intracellular siRNA kinetics is achievable. A tailored NSC design delivering survivin-siRNA can extend the survivin knockdown period to 9 days, translating into steady, effective in vitro and in vivo chemosensitization of prostate cancer to docetaxel for over a week. All in all, this new NSC design provides a convenient mean to set up a clinically more appealing weekly or longer dosing cycle for siRNA therapy, which addresses a significant unmet need for prostate cancer treatment and is potentially useful for other chronic disease conditions as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Docetaxel
  • Drug Carriers / chemistry*
  • Drug Resistance, Neoplasm / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism*
  • Kinetics
  • Lipids / chemistry*
  • Microscopy, Fluorescence
  • Nanostructures / chemistry*
  • Nanotechnology / methods*
  • Particle Size
  • RNA Interference* / drug effects
  • RNA, Small Interfering / metabolism*
  • Static Electricity
  • Sterol Esterase / metabolism
  • Survivin
  • Taxoids / pharmacology
  • Time Factors

Substances

  • BIRC5 protein, human
  • Drug Carriers
  • Inhibitor of Apoptosis Proteins
  • Lipids
  • RNA, Small Interfering
  • Survivin
  • Taxoids
  • Docetaxel
  • Sterol Esterase