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

Research output: Contribution to journalArticle

12 Scopus citations

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 N1,N11-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 N1-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.

Original languageEnglish (US)
Pages (from-to)332-341
Number of pages10
JournalMolecular Pharmaceutics
Volume12
Issue number2
DOIs
StatePublished - Feb 2 2015

Keywords

  • TNFα
  • bisethylnorspermine
  • combination therapy
  • gene delivery
  • polyamine metabolism
  • polymeric prodrugs
  • self-immolative linker

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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