In silico, in vitro, and in vivo studies indicate the potential use of bolaamphiphiles for therapeutic siRNAs delivery

Taejin Kim, Kirill A. Afonin, Mathias Viard, Alexey Y. Koyfman, Selene Sparks, Eliahu Heldman, Sarina Grinberg, Charles Linder, Robert P. Blumenthal, Bruce A. Shapiro

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Specific small interfering RNAs (siRNAs) designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biologicalmembranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholinehead groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAsand deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD) simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silicostudies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used.

Original languageEnglish
Article numbere80
Pages (from-to)e80
JournalMolecular Therapy - Nucleic Acids
Volume2
DOIs
StatePublished - 1 Jan 2013

Keywords

  • Bolaamphiphiles
  • Cryo-EM
  • FRET
  • Molecular dynamics simulations
  • Poly-cationic micelles
  • RNA-based therapeutics
  • SiRNA delivery
  • Specific gene silencing

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