Slow release of etoposide from dextran conjugation shifts etoposide activity from cytotoxicity to differentiation: A promising tool for dosage control in anticancer metronomic therapy

Milena De Nicola, Emanuele Bruni, Enrico Traversa, Lina Ghibelli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Drug conjugation, improving drug stability, solubility and body permanence, allows achieving impressive results in tumor control. Here, we show that conjugation may provide a straightforward method to administer drugs by the emerging anticancer metronomic approach, presently consisting of low, repeated doses of cytotoxic drugs used in traditional chemotherapy, thus reducing toxicity without reducing efficiency; however, low dose maintenance in tumor sites is difficult. We show that conjugating the antitumor drug etoposide to dextran via pH-sensitive bond produces slow releasing, apoptosis-proficient conjugates rapidly internalized into acidic lysosomes; importantly, release of active etoposide requires cell internalization and acidic pH. Conjugation, without impairing etoposide-induced complete elimination of tumor cells, shifted the mode of apoptosis from cytotoxicity- to differentiation-related; interestingly, high conjugate doses acted as low doses of free etoposide, thus mimicking the effect of metronomic therapy. This indicates slow release as a promising novel strategy for stabilizing low drug levels in metronomic regimens.

Original languageEnglish (US)
Pages (from-to)2005-2014
Number of pages10
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume13
Issue number6
DOIs
StatePublished - Aug 1 2017

Keywords

  • Apoptosis
  • Drug conjugation
  • Etoposide
  • Metronomic anticancer therapy

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Bioengineering
  • Biomedical Engineering
  • Molecular Medicine
  • Materials Science(all)
  • Pharmaceutical Science

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