HER-2-mediated nano-delivery of molecular targeted drug potently suppresses orthotopic epithelial ovarian cancer and metastasis

Abstract

The treatment of epithelial ovarian cancer (EOC) has made slow progress due to absence of effective adjuvant chemotherapy that is capable of preventing tumor relapse and metastasis. Molecular targeted drugs such as PARP and PLK1 inhibitors appear to be promising new treatments for EOC. The low EOC cell uptake, poor selectivity and pronounced toxicity, however, greatly compromise their clinical efficacy. Herein, we report that HER-2-mediated nano-delivery of clinical PLK1-targeted drug, volasertib (Vol), while causing little toxicity potently suppresses orthotopic EOC and metastasis. Anti-HER-2 antibody, trastuzumab (Tra), was conjugated onto Vol-loaded polymersomes via click chemistry yielding Tra-PVol with a size of 33 nm and optimally about 5 Tra per polymersome. Tra-PVol exhibited clearly stronger uptake and anti-tumor activity (IC₅₀ = 59 nM) in HER-2 overexpressing SKOV-3 cells than free Vol and non-targeted PVol controls. Both biodistribution and therapeutic studies in orthotopic SKOV-3-Luc tumor-bearing mice displayed that Tra-PVol induced significantly better tumor deposition and retardation than PVol and that intraperitoneal administration outperformed intravenous administration. More interestingly, Tra-PVol was shown to effectively suppress the intraperitoneal metastasis and to markedly prolong the survival time of SKOV-3-Luc tumor-bearing mice. This HER-2 directed molecular therapy emerges as a potential treatment strategy toward EOC.

Keywords: Adjuvant chemotherapy; Cancer metastasis; Epithelial ovarian cancer; HER-2; Intraperitoneal administration; Polymersomes; Targeted therapy; Trastuzumab.