Self-organized environment-sensitive inulin–doxorubicin conjugate with a selective cytotoxic effect towards cancer cells

• Published in: RSC advances 2015-01, Vol.5 (41), p.32421-32430
• Main Authors: Mauro, N., Campora, S., Scialabba, C., Adamo, G., Licciardi, M., Ghersi, G., Giammona, G.
• Format: Article
• Language: English
• Subjects: Aptitude; Cancer; Conjugates; Copolymers; Doxorubicin; Drug delivery systems; Stacking
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/C5RA00287G

An inulin-based random copolymer bearing high dose doxorubicin (18.45% on a weight basis), INU-EDA-P,C-DOXO, was prepared by coupling doxorubicin with inulin though a citraconylamide bridge used as a pH sensitive spacer. A further conjugation with pentynoic acid via an amidic bond led to the hydrophobization of the copolymer which allows the acquisition of a self-assembling ability at low concentration (0.33 mg mL −1 ) combining both Π–Π stacking and London interactions. Drug release studies were carried out at different pH demonstrating a remarkable pH dependency, where the maximum release rate was observed at pH mimicking cancer tissue and lysosomal environments. Besides, by measuring ζ -potential variations as a function of the pH, INU-EDA-P,C-DOXO proved capable of undergoing charge reversal at acidic pH, changing its physicochemical and biological behavior. In vitro tests with cancer (MDA-MB 231) and normal (HB-2) breast cells were carried out to verify the conjugate aptitude to follow different routes to enter cells depending on the microenvironment. This finding was supported by quantitative up-take studies, which revealed that INU-EDA-P,C-DOXO released doxorubicin before entering cancer cells, as the entire copolymer diffused across normal cell membranes without relevant modifications.