Polymer−Drug Conjugates for Combination Anticancer Therapy: Investigating the Mechanism of Action

We developed a family of polymer−drug conjugates carrying the combination of the anticancer agent epirubicin (EPI) and nitric oxide (NO). EPI-PEG-(NO)8, carrying the highest content of NO, displayed greater activity in Caco-2 cells while it decreased toxicity against endothelium cells and cardiomyoc...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-10, Vol.52 (20), p.6499-6502
Hauptverfasser:	Pasut, Gianfranco, Greco, Francesca, Mero, Anna, Mendichi, Raniero, Fante, Cristina, Green, Rebecca J, Veronese, Francesco M
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols Biological and medical sciences Biological Transport Cell Line, Tumor Epirubicin - administration & dosage Epirubicin - chemistry Epirubicin - pharmacokinetics Epirubicin - pharmacology General aspects Humans Lipid Metabolism Medical sciences Mice Nitric Oxide - chemistry Nitric Oxide - metabolism Pharmacology. Drug treatments Polyethylene Glycols - chemistry Solutions Structure-Activity Relationship
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Zusammenfassung:	We developed a family of polymer−drug conjugates carrying the combination of the anticancer agent epirubicin (EPI) and nitric oxide (NO). EPI-PEG-(NO)8, carrying the highest content of NO, displayed greater activity in Caco-2 cells while it decreased toxicity against endothelium cells and cardiomyocytes with respect to free EPI. FACS and confocal microscopy confirmed conjugates internalization. Light scattering showed formation of micelle whose size correlated with internalization rate. EPI-PEG-(NO)8 showed increased bioavailability in mice compared to free EPI.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm900804m