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 journalArticlepeer-review

18 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
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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