Ovarian cancer is the leading cause of death from gynecologic malignancy. Most women are diagnosed with metastatic ovarian cancer, and the 5-year survival rate for this late stage disease is less than 28%. The mainstay of treatment for ovarian cancer entails debulking cytoreductive surgery in combination with adjuvant chemotherapies. Unfortunately, severe side effects of these chemotherapies compromise the quality of life and result in poor patient compliance, and the relapse rate is high due to intrinsic and acquired therapy resistance. Therefore, there is a pressing need for the development of new safe and effective treatment strategies. Our group has developed a novel pH and redox potential dual responsive polymer, poly[(2-(pyridin- 2-yldisulfanyl)-co-[poly(ethylene glycol)]] (PDA-PEG), which can be degraded intracellularly. If used as a drug carrier, this polymer system significantly improves the cancer cell killing effect and potentially reduces the off- target toxicity of the carried chemotherapeutic drugs. More excitingly, follow-up studies revealed that the combination of PDA-PEG and copper ions, termed polymer-metal nanocomplex (PMC), without being loaded with any chemotherapeutic drugs, could effectively kill a large variety of cancer cells, including drug-resistant ovarian cancer cells. Importantly, the PMC showed excellent cancer cell-selective killing; it could induce apoptosis in various cancer cells with a 30-100-fold improved IC50 over non-cancer cells. Furthermore, a preliminary study showed that PMC significantly inhibited tumor growth in an ovarian cancer mouse model. Based on these technology advancements and exciting in vitro and in vivo results, we propose to develop the PDA-PEG/Cu PMC into a novel safe and effective therapy for ovarian cancer and possible other malignant tumors. In this STTR Phase I project, we propose two specific aims. SA1. To test the toxicity of the PDA- PEG/Cu PMC in vitro and in vivo. Since besides in the tumors, PMC may also accumulate in the liver and the reticuloendothelial system, we will test the toxicity of the PMC on primary mouse cells including bone morrow- derived macrophages and dendritic cells, T cells, vascular endothelial cells, and hepatocytes, as well commercially available human primary cells including hepatocytes, vascular endothelial cells and mononuclear cells. We will then test the in vivo toxicity of PMC in tumor-free C57Bl/6 mice and Balb/c mice. SA2. To test the in vivo efficacy of the PDA-PEG/Cu PMC in treating metastatic ovarian cancer. We will test the efficacy of PMC in treating peritoneal metastatic ovarian cancer when PMC is administered intraperitoneally, compared to cisplatin. A syngeneic ovarian cancer mouse model (C57Bl/6 mice inoculated with ID8-Luc cells) will be used; therefore, we will be able to access the efficacy of PMC in the presence of host immune response. We will also examine if PMC and cisplatin result in synergistic benefit. The efficacy and toxicity of PMC also will be tested using a humanized mouse model (CD34+ HU-NSGTM) transplanted with patient-derived ovarian tumors.
Ovarian cancer is estimated to cause 13,980 deaths in American women in 2019, new safe and effective treatment strategies are urgently needed. This research will develop a novel patented polymer-metal nanocomplex system for the treatment of ovarian cancer. The success of this project will provide a new tool to fight against the devastating disease.
