A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer

JOURNAL OF CONTROLLED RELEASE

卷:236

Article

Montagner, Isabella Monia¹  Merlo, Anna¹  Carpanese, Debora²  Pieta, Anna Dalla²  Mero, Anna³  Grigoletto, Antonella³  Loregian, Arianna⁴  Renier, Davide⁵  Campisi, Monica⁵  Zanovello, Paola^1,2  Pasut, Gianfranco^1,3  Rosato, Antonio^1,2 

[1] Veneto Inst Oncol IOV IRCCS, Padua, Italy

[2] Univ Padua, Dept Surg Oncol & Gastroenterol, Via Gattamelata 64, I-35128 Padua, Italy

[3] Univ Padua, Dept Pharmaceut & Pharmacol Sci, Via F Marzolo 5, I-35131 Padua, Italy

[4] Univ Padua, Dept Mol Med, Padua, Italy

[5] Fidia Farmaceut SpA, Abano Terme, Italy

关键词: Ovarian cancer;    Tumor targeting;    Interferon;    HAylation;    Hyaluronan;   

DOI  :  10.1016/j.jconrel.2016.06.033

来源: Elsevier

【 摘 要 】

While interferon alpha (IFN alpha) 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 IFN alpha 2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFN alpha 2a bioconjugate was biochemically and biologically characterized. The conjugation with HA did not substantiallymodified 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-IFN alpha 2a persisted into the peritoneal cavity longer than IFN alpha 2a without being toxic for intraperitoneal organs, thus potentially enhancing the loco-regional therapeutic effect. Indeed, in OC xenograftmouse models bioconjugate significantly improved survival as compared to the free cytokine. Overall, HA-IFN alpha 2a bioconjugate disclosed an improved anticancer efficacy, and can be envisaged as a promising loco-regional treatment for OC. (C) 2016 The Authors. Published by Elsevier B.V.

【 授权许可】

Free