Synthesis of bisethylnorspermine lipid prodrug as gene delivery vector targeting polyamine metabolism in breast cancer

Yanmei Dong, Yu Zhu, Jing Li, Qing Hui Zhou, Chao Wu, David Oupický

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery.

Original languageEnglish (US)
Pages (from-to)1654-1664
Number of pages11
JournalMolecular Pharmaceutics
Volume9
Issue number6
DOIs
StatePublished - Jun 4 2012

Keywords

  • TRAIL
  • bisethylnorspermine
  • cationic lipid
  • gene delivery
  • plasmid DNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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