Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy

Ying Xie, Tracy Murray-Stewart, Yazhe Wang, Fei Yu, Jing Li, Laurence J. Marton, Robert A. Casero, David Oupicky

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.

Original languageEnglish (US)
Pages (from-to)110-119
Number of pages10
JournalJournal of Controlled Release
Volume246
DOIs
StatePublished - Jan 28 2017

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Keywords

  • Bisethylnorspermine
  • Cancer
  • Combination delivery
  • Nanoparticles
  • Polyamine metabolism
  • Polyplexes
  • Self-immolative polymer
  • miRNA

ASJC Scopus subject areas

  • Pharmaceutical Science

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