Montagner Isabella Monia, Merlo Anna, Carpanese Debora, Zuccolotto Gaia, Renier Davide, Campisi Monica, Pasut Gianfranco, Zanovello Paola, Rosato Antonio
Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Oncoscience. 2015 Mar 23;2(4):373-81. doi: 10.18632/oncoscience.150. eCollection 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.
卵巢癌的治疗仍需改进治疗方案。一种药物递送策略经过测试，该策略可实现肿瘤细胞的特异性靶向，并结合细胞毒性分子的控释。为此，在卵巢癌腹膜转移小鼠模型中评估了一种生物共轭物（ONCOFID-S）的局部区域腹腔内治疗效果，该生物共轭物由伊立替康（CPT-11）的活性代谢产物SN-38与透明质酸化学连接而成。在体外，该生物共轭物通过CD44受体与卵巢癌细胞选择性相互作用，显示出与游离SN-38药物相当的剂量依赖性肿瘤生长抑制效果，并通过涉及半胱天冬酶-3和-7激活以及PARP裂解的机制抑制拓扑异构酶I功能，导致细胞凋亡。在体内，向荷瘤小鼠腹腔内注射ONCOFID-S未引发炎症，且与CPT-11相比，显示出更高的治疗效果。总之，SN-38与透明质酸的共轭显著改善了体内耐受性，并拓宽了伊立替康的应用范围。因此，这种方法可被视为一种有前景的卵巢癌局部区域治疗策略。
