title: Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer.
abstract: Management of ovarian cancer still requires improvements in therapeutic options. A drug delivery strategy was tested that allows specific targeting of tumor cells in combination with a controlled release of a cytotoxic molecule. To this aim, the efficacy of a loco-regional intraperitoneal treatment with a bioconjugate (ONCOFID-S) derived by chemical linking of SN-38, the active metabolite of irinotecan (CPT-11), to hyaluronan was assessed in a mouse model of ovarian carcinomatosis. In vitro, the bioconjugate selectively interacted with ovarian cancer cells through the CD44 receptor, disclosed a dose-dependent tumor growth inhibition efficacy comparable to that of free SN-38 drug, and inhibited Topoisomerase I function leading to apoptosis by a mechanism involving caspase-3 and -7 activation and PARP cleavage. In vivo, the intraperitoneal administration of ONCOFID-S in tumor-bearing mice did not induce inflammation, and evidenced an improved therapeutic efficacy compared with CPT-11. In conclusion, SN-38 conjugation to hyaluronan significantly improved the profile of in vivo tolerability and widened the field of application of irinotecan. Therefore, this approach can be envisaged as a promising therapeutic strategy for loco-regional treatment of ovarian cancer.
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 Medicine, University of Padua, Padua, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Zuccolotto
authors.affiliation: Fidia Farmaceutici S.p.A, Abano Terme, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Renier
authors.affiliation: Fidia Farmaceutici S.p.A, Abano Terme, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Campisi
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
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.
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.affiliation: Veneto Institute of Oncology IOV - IRCCS, Padua, Italy ; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
keywords: SN-38; bioconjugate; hyaluronan; ovarian cancer; tumor targeting