Synthesis and characterization of degradable multivalent cationic lipids with disulfide-bond spacers for gene delivery

Rahau S. Shirazi, Kai K. Ewert, Cecilia Leal, Ramsey N. Majzoub, Nathan F. Bouxsein, Cyrus R. Safinya

Research output: Contribution to journalArticle

Abstract

Gene therapy provides powerful new approaches to curing a large variety of diseases, which are being explored in ongoing worldwide clinical trials. To overcome the limitations of viral gene delivery systems, synthetic nonviral vectors such as cationic liposomes (CLs) are desirable. However, improvements of their efficiency at reduced toxicity and a better understanding of their mechanism of action are required. We present the efficient synthesis of a series of degradable multivalent cationic lipids (CMVLn, n = 2 to 5) containing a disulfide bond spacer between headgroup and lipophilic tails. This spacer is designed to be cleaved in the reducing milieu of the cytoplasm and thus decrease lipid toxicity. Small angle X-ray scattering demonstrates that the initially formed lamellar phase of CMVLn-DNA complexes completely disappears when reducing agents such as DTT or the biologically relevant reducing peptide glutathione are added to mimic the intracellular milieu. The CMVLs (n = 3 to 5) exhibit reduced cytotoxicity and transfect mammalian cells with efficiencies comparable to those of highly efficient non-degradable analogs and benchmark commercial reagents such as Lipofectamine 2000. Thus, our results demonstrate that degradable disulfide spacers may be used to reduce the cytotoxicity of synthetic nonviral gene delivery carriers without compromising their transfection efficiency.

Original languageEnglish (US)
Pages (from-to)2156-2166
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1808
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • Cationic lipid
  • Cationic liposome
  • Gene delivery
  • Nonviral

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Biophysics

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