The efficacy of nuclease-resistant Chol-siRNA in primary breast tumors following complexation with PLL-PEG(5K)

Vishakha V. Ambardekar, Rajesh R. Wakaskar, Bhawna Sharma, Joy Bowman, Willy Vayaboury, Rakesh K. Singh, Joseph A. Vetro

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Modifying the sense strand of nuclease-resistant siRNA with 3'-cholesterol (Chol-*siRNA) increases mRNA suppression after i.v. administration but with relatively low efficacy. We previously found evidence invitro that suggests complexation of Chol-siRNA with PLL-PEG(5K), a block copolymer of poly- l-lysine and 5kDa polyethylene glycol, may increase the efficacy of Chol-siRNA invivo in a PLL block length-dependent manner. In this study, the extent that polyplexes of PLL10-PEG(5K), PLL30-PEG(5K), and PLL50-PEG(5K) protect complexed Chol-siRNA in high concentrations of murine serum and affect the activity of Chol-*siRNA in murine 4T1 breast tumor epithelial cells invitro and in primary orthotopic tumors of 4T1 was compared. PLL-PEG(5K) required 3'-Chol to protect full-length siRNA from nuclease degradation in 90% (v/v) murine serum and protection was increased by increasing PLL block length and nuclease resistance of Chol-siRNA. Polyplexes of Chol-*siLuc suppressed stably expressed luciferase in 4T1-Luc cells to different levels invitro where PLL30>PLL50>PLL10. In contrast, only polyplexes of Chol-*siLuc and PLL30-PEG(5K) or PLL50-PEG(5K) suppressed high levels of luciferase in primary orthotopic tumors of 4T1-Luc after i.v. administration, whereas polyplexes of Chol-*siLuc and PLL10-PEG(5K), inactive Chol-*siCtrl polyplexes of PLL-PEG(5K), or Chol-*siLuc alone had no detectable activity. As a whole, these results indicate that polyplexes of PLL-PEG(5K) increase the efficacy of nuclease-resistant Chol-siRNA in primary breast tumors after i.v. administration in a PLL block length-dependent manner. Thus, complexation of Chol-siRNA with PLL-PEG(5K) may be a promising approach to increase the efficacy of Chol-siRNA in a wide range of primary tumors, metastases, and other tissues but likely requires a PLL block length that balances polymer-related adverse effects, Chol-siRNA bioavailability, and subsequent activity in the target cell.

Original languageEnglish (US)
Pages (from-to)4839-4848
Number of pages10
JournalBiomaterials
Volume34
Issue number20
DOIs
StatePublished - Jul 2013

Keywords

  • Drug delivery
  • Polymer siRNA complexes
  • RNA interference
  • RNAi
  • SiRNA delivery
  • SiRNA polyplexes

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Fingerprint Dive into the research topics of 'The efficacy of nuclease-resistant Chol-siRNA in primary breast tumors following complexation with PLL-PEG(5K)'. Together they form a unique fingerprint.

Cite this