Molecular Pharmaceutics 2015-02-02

Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer.

Yu Zhu, Jing Li, Shrey Kanvinde, Zhiyi Lin, Stuart Hazeldine, Rakesh K Singh, David Oupický

Index: Mol. Pharm. 12(2) , 332-41, (2015)

Full Text: HTML

Abstract

Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N(1),N(11)-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N(1)-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNFα-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNFα gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer.


Related Compounds

Related Articles:

L. monocytogenes in a cheese processing facility: Learning from contamination scenarios over three years of sampling.

2014-10-17

[Int. J. Food Microbiol. 189 , 98-105, (2014)]

Alpha-fetoprotein, identified as a novel marker for the antioxidant effect of placental extract, exhibits synergistic antioxidant activity in the presence of estradiol.

2014-01-01

[PLoS ONE 9(6) , e99421, (2014)]

Vegetables' juice influences polyol pathway by multiple mechanisms in favour of reducing development of oxidative stress and resultant diabetic complications.

2014-04-01

[Pharmacogn. Mag. 10(Suppl 2) , S383-91, (2014)]

Glucose recognition proteins for glucose sensing at physiological concentrations and temperatures.

2014-07-18

[ACS Chem. Biol. 9(7) , 1595-602, (2014)]

Reservoirs of listeria species in three environmental ecosystems.

2014-09-01

[Appl. Environ. Microbiol. 80(18) , 5583-92, (2014)]

More Articles...