An intraperitoneal implantable drug delivery device for the treatment of ovarian cancer

Abstract

Ovarian cancer is the fifth leading cause of cancer-related deaths in women and the deadliest gynecologic cancer. The current standard treatment for advanced ovarian cancer includes a minimally invasive cytoreduction surgery, followed by intravenous (IV) or intraperitoneal (IP) chemotherapy with cisplatin and taxol. Clinical trials showed that the IP cisplatin treatment regimen was able to prolong overall survival by 16 months but only 42% of subjects completed all cycles of the IP therapy. The primary reason for the early termination of the IP treatment is catheter-related complications. The implantation of the catheter is also a complex procedure that can only be performed at premier centers by trained personnel. An alternative for IP administration that eliminates catheter-related complications and simplifies IP drug administration would therefore allow more patients to enjoy the benefits of IP therapy. A drug delivery device for use in a mouse model was developed as a tool to prove that maintaining a low constant cisplatin concentration in the peritoneal cavity and serum would improve the treatment outcome and reduce drug-related toxicity in ovarian cancer, compared to periodic IP bolus drug infusion. The device demonstrated highly linear and easily tunable in vitro release and exhibited excellent in vitro-in vivo correlation. Investigations of the device pharmacokinetics in vivo proved that the device was able to maintain a low and constant cisplatin concentration both locally in the peritoneal cavity and in the serum over up to six weeks. In vitro cytotoxicity of continuous cisplatin dosing with various human ovarian cancer cells lines was demonstrated. An in vivo xenograft SKOV-3 tumor model was established and optimized to reflect the distribution of ovarian cancer metastases in humans. The device achieved effective tumor growth retardation without systemic toxicity. An IP bolus injection scheme with a similar area-under-curve (AUC), however, caused severe bone marrow depletion. The results verified that the treatment efficacy correlates with the AUC but not the peak concentration, Cma. These promising preclinical results highlight the potential of this new therapeutic regimen to change the course of ovarian cancer care and warrant the need for designing a human device before proceeding to human trials.