Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano 11047

Tracy Murray-Stewart, Elena Ferrari, Ying Xie, Fei Yu, Laurence J. Marton, David Oupicky, Robert A. Casero

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target polyamine metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation polyamine analogue PG-11047. Polyamines are absolutely essential for proliferation and their metabolism is frequently dysregulated in cancer. Through its effects on polyamine metabolism, PG-11047 effectively inhibits tumor growth in cancer cell lines of multiple origins as well as in human tumor mouse xenografts. Promising clinical trials have been completed verifying the safety and tolerance of this rotationally restricted polyamine analogue. We therefore used PG-11047 as the basis for Nano11047, a biodegradable, prodrug nanocarrier capable of targeting polyamine metabolism. Following exposure of lung cancer cell lines to Nano11047, uptake and intracellular degradation into the parent compound PG-11047 was observed. The release of PG-11047 highly induced the polyamine catabolic enzyme activities of spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX). By contrast, the activity of ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine biosynthesis and a putative oncogene, was decreased. Consequently, intracellular levels of the natural polyamines were depleted concurrent with tumor cell growth inhibition. This availability of Nano11047 as a novel drug form and potential nucleic acid delivery vector will potentially benefit and encourage future clinical studies.

Original languageEnglish (US)
Article numbere0175917
JournalPloS one
Volume12
Issue number4
DOIs
StatePublished - Apr 2017

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Polyamines
polyamines
Metabolism
Tumors
metabolism
spermine
Neoplasms
drugs
Nucleic Acids
nucleic acids
neoplasms
clinical trials
Cells
cell lines
nanocarriers
Pharmaceutical Preparations
Cell Line
ornithine decarboxylase
biodegradability
acetyltransferases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Murray-Stewart, T., Ferrari, E., Xie, Y., Yu, F., Marton, L. J., Oupicky, D., & Casero, R. A. (2017). Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano 11047. PloS one, 12(4), [e0175917]. https://doi.org/10.1371/journal.pone.0175917

Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano 11047. / Murray-Stewart, Tracy; Ferrari, Elena; Xie, Ying; Yu, Fei; Marton, Laurence J.; Oupicky, David; Casero, Robert A.

In: PloS one, Vol. 12, No. 4, e0175917, 04.2017.

Research output: Contribution to journalArticle

Murray-Stewart, T, Ferrari, E, Xie, Y, Yu, F, Marton, LJ, Oupicky, D & Casero, RA 2017, 'Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano 11047', PloS one, vol. 12, no. 4, e0175917. https://doi.org/10.1371/journal.pone.0175917
Murray-Stewart, Tracy ; Ferrari, Elena ; Xie, Ying ; Yu, Fei ; Marton, Laurence J. ; Oupicky, David ; Casero, Robert A. / Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano 11047. In: PloS one. 2017 ; Vol. 12, No. 4.
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