Unknown

Dataset Information

0

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


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 TNF?-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNF? 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.

SUBMITTER: Zhu Y 

PROVIDER: S-EPMC4319695 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Zhu Yu Y   Li Jing J   Kanvinde Shrey S   Lin Zhiyi Z   Hazeldine Stuart S   Singh Rakesh K RK   Oupický David D  

Molecular pharmaceutics 20140825 2


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  ...[more]

Similar Datasets

| S-EPMC5258827 | biostudies-literature
| S-EPMC6538062 | biostudies-literature
| S-EPMC10170519 | biostudies-literature
| S-EPMC8434617 | biostudies-literature
| S-EPMC7660303 | biostudies-literature
| S-EPMC5711482 | biostudies-literature
| S-EPMC9268001 | biostudies-literature
| S-EPMC3879331 | biostudies-literature
| S-EPMC6247628 | biostudies-literature
| S-EPMC5844511 | biostudies-literature