Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer
Isabella Monia Montagner1, Anna Merlo1, Debora Carpanese2, Gaia Zuccolotto3, Davide Renier4, Monica Campisi4, Gianfranco Pasut5, Paola Zanovello1,2, Antonio Rosato1,2
1 Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
2 Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
3 Department of Medicine, University of Padua, Padua, Italy
4 Fidia Farmaceutici S.p.A, Abano Terme, Italy
5 Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
Antonio Rosato, email:
Keywords: ovarian cancer, tumor targeting, SN-38, hyaluronan, bioconjugate
Received: January 20, 2015 Accepted: March 16, 2015 Published: March 23, 2015
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.