title: A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer.
abstract: 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.
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: Isabella Monia
authors.initials: IM
authors.lastname: Montagner
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Merlo
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Carpanese
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Dalla Pietà
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mero
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Grigoletto
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Loregian
authors.affiliation: Fidia Farmaceutici SpA, Abano Terme, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Renier
authors.affiliation: Fidia Farmaceutici SpA, Abano Terme, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Campisi
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy. Electronic address: gianfranco.pasut@unipd.it.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. Electronic address: antonio.rosato@unipd.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D006820:Hyaluronic Acid
keywords: HAylation; Hyaluronan; Interferon; Ovarian cancer; Tumor targeting