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 language | English (US) |
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Pages (from-to) | 2005-2014 |
Number of pages | 10 |
Journal | Nanomedicine: Nanotechnology, Biology, and Medicine |
Volume | 13 |
Issue number | 6 |
DOIs | |
State | Published - Aug 2017 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2017 Elsevier Inc.
Keywords
- Apoptosis
- Drug conjugation
- Etoposide
- Metronomic anticancer therapy
ASJC Scopus subject areas
- Bioengineering
- Molecular Medicine
- Biomedical Engineering
- General Materials Science
- Medicine (miscellaneous)
- Pharmaceutical Science