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 language | English (US) |
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Pages (from-to) | 1654-1664 |
Number of pages | 11 |
Journal | Molecular Pharmaceutics |
Volume | 9 |
Issue number | 6 |
DOIs | |
State | Published - Jun 4 2012 |
Externally published | Yes |
Keywords
- TRAIL
- bisethylnorspermine
- cationic lipid
- gene delivery
- plasmid DNA
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery