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

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.
Authors	Yanmei Dong, Yu Zhu, Jing Li, Qing-Hui Zhou, Chao Wu, David Oupický
Journal	Molecular pharmaceutics (Mol Pharm) Vol. 9 Issue 6 Pg. 1654-64 (Jun 04 2012) ISSN: 1543-8392 [Electronic] United States
PMID	22545813 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Polyamines Prodrugs TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Spermine
Topics	Animals Breast Neoplasms Cell Line, Tumor Cell Survival (drug effects) Gene Transfer Techniques Genetic Vectors Humans Magnetic Resonance Spectroscopy Mice Polyamines (chemical synthesis, pharmacology) Prodrugs (chemical synthesis, pharmacology) Spectrometry, Mass, Electrospray Ionization Spermine (analogs & derivatives, chemical synthesis, pharmacology) TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism, pharmacology)

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