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.

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

“…Therefore, HA can act as a suitable carrier being endowed with the capability to selectively target tumor cells through the binding to CD44. This receptor is over-expressed in many cancers, including the ovarian histotype as exemplified by cytometry results outlined in this work and previously [26,43]. Moreover, it has been shown that HA has per se the capacity to reduce postoperative and disease-related adhesions without impacting the metastatic potential of tumor cells [44].…”

“…In addition, the bioconjugate was also very efficient towards different models of peritoneal carcinomatosis [26], and bladder cancer both in experimental [25] and clinical conditions [41]. Moreover, another HA bioconjugate (SN38-HA) has been successfully tested in a mouse model of CRC peritoneal carcinomatosis [42] and OC [43]. Therefore, HA can act as a suitable carrier being endowed with the capability to selectively target tumor cells through the binding to CD44.…”

Hyaluronan: molecular size‐dependent signaling and biological functions in inflammation and cancer

“…developed a technological platform for the chemical conjugation of 200 kDa HA with well‐known anticancer drugs such as paclitaxel and SN‐38 (active metabolite of irinotecan). These coupled molecules, named Oncofid P (formerly HYTAD1‐P20) and Oncofid S, respectively, were shown to be active in vitro toward CD44‐overexpressing human bladder and ovarian cancer cell lines, thanks to the receptor‐mediated internalization of the anticancer drug, favored by HA conjugation . The safety and effectiveness of the HA–anticancer drug conjugates were then confirmed in vivo in different tumor animal models and lastly the Oncofid P therapy against bladder cancer entered the clinical evaluation phase .…”

“…Furthermore, s-HA suppresses tumor growth in xenograft models of both cancer types without toxic side-effects [250,251]. An intriguing application of small HA fragments is their use in the construction of nanocarrier for targeted cancer therapy [252] [245,246] named Oncofid P (formerly HYTAD1-P20) and Oncofid S, respectively, were shown to be active in vitro toward CD44-overexpressing human bladder and ovarian cancer cell lines, thanks to the receptor-mediated internalization of the anticancer drug, favored by HA conjugation [255,256]. The safety and effectiveness of the HA-anticancer drug conjugates were then confirmed in vivo in different tumor animal models [257,258] and lastly the Oncofid P therapy against bladder cancer entered the clinical evaluation phase [259].…”

Hyaluronan as a therapeutic target in human diseases

“…HA conjugation significantly increased drug uptake and extended the residence time of drugs in tumor cells in mice [263]. For example, conjugation of irinotecan to HA significantly improved the profile of in vivo tolerability for ovarian cancer [264]. Conjugation of paclitaxel improved therapeutic efficacy for peritoneal tumor carcinomatosis [265] and ovarian cancer [266].…”