Design of an intraperitoneal drug-release device for advanced ovarian cancer therapy

Abstract

More than 14,000 women in the United States die from ovarian cancer each year. The standard of care is tumor-debulking surgery followed by adjuvant chemotherapy. Combination intraperitoneal (IP) and intravenous (IV) chemotherapy has been shown to lengthen survival over IV therapy alone. Large-volume infusions, drug-associated toxicity, and catheter-associated complications, however, increase morbidity and limit patient adherence, often resulting in discontinuation of IP therapy. The technical skill required for catheter implantation and IP chemotherapy administration has also limited its clinical adoption. The proposed solution is an implantable IP device capable of localized drug delivery that maintains the efficacy of the standard of care and overcomes current clinical challenges. A reservoir-based device was developed to release cisplatin at a constant rate. In vivo studies demonstrated that continuous dosing reduces tumor burden to the same extent as weekly IP injections. The implanted device induced significantly less systemic toxicity compared to IP injections, despite administration of higher cumulative doses. A subsequent in vitro study revealed that greater tumor shrinkage following continuous cisplatin exposure was achieved with smaller tumor nodules. These results support that an implanted device would be maximally effective against microscopic residual disease. In vitro results also illustrated that a human-scale device fabricated from orifice-lined silicone can be designed to release cisplatin continuously at the desired rate. The promising preclinical results in this thesis highlight the potential for this novel IP dosing regimen to improve the treatment of late-stage ovarian cancer and set the stage for development of the proposed human device.