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. (C) 2017 Elsevier Inc. All rights reserved.

De Nicola, M., Bruni, E., Traversa, E., Ghibelli, L. (2017). Slow release of etoposide from dextran conjugation shifts etoposide activity from cytotoxicity to differentiation: A promising tool for dosage control in anticancer metronomic therapy. NANOMEDICINE, 13(6), 2005-2014 [10.1016/j.nano.2017.05.004].

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

Traversa E.;Ghibelli L.
2017

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. (C) 2017 Elsevier Inc. All rights reserved.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13
English
Apoptosis; Drug conjugation; Etoposide; Metronomic anticancer therapy; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Differentiation; Cells, Cultured; Dextrans; Etoposide; Humans; Monocytes; Neoplasms
De Nicola, M., Bruni, E., Traversa, E., Ghibelli, L. (2017). Slow release of etoposide from dextran conjugation shifts etoposide activity from cytotoxicity to differentiation: A promising tool for dosage control in anticancer metronomic therapy. NANOMEDICINE, 13(6), 2005-2014 [10.1016/j.nano.2017.05.004].
De Nicola, M; Bruni, E; Traversa, E; Ghibelli, L
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/241862
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