TY - JOUR
T1 - A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer
AU - Montagner, Isabella Monia
AU - Merlo, Anna
AU - Carpanese, Debora
AU - Dalla Pietà, Anna
AU - Mero, Anna
AU - Grigoletto, Antonella
AU - Loregian, Arianna
AU - Renier, Davide
AU - Campisi, Monica
AU - Zanovello, Paola
AU - Pasut, Gianfranco
AU - Rosato, Antonio
PY - 2016/8/28
Y1 - 2016/8/28
N2 - While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantially modified both the antiviral function and the anti-proliferative activity of the cytokine. Moreover, the induction of STAT1 phosphorylation and of a specific gene expression signature in different targets was retained. In vivo optical imaging biodistribution showed that the i.p.-injected HA-IFNα2a persisted into the peritoneal cavity longer than IFNα2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograft mouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFNα2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC.
AB - While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantially modified both the antiviral function and the anti-proliferative activity of the cytokine. Moreover, the induction of STAT1 phosphorylation and of a specific gene expression signature in different targets was retained. In vivo optical imaging biodistribution showed that the i.p.-injected HA-IFNα2a persisted into the peritoneal cavity longer than IFNα2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograft mouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFNα2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC.
KW - HAylation
KW - Hyaluronan
KW - Interferon
KW - Ovarian cancer
KW - Tumor targeting
UR - http://www.scopus.com/inward/record.url?scp=84976584770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84976584770&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2016.06.033
DO - 10.1016/j.jconrel.2016.06.033
M3 - Article
AN - SCOPUS:84976584770
VL - 236
SP - 79
EP - 89
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -