Sustained-release implants for intraperitoneal cisplatin delivery

Abstract

The objective of this work was to develop materials for continuous low-dose delivery of cisplatin directly into the abdomen, also known as intraperitoneal (IP) chemotherapy. IP chemotherapy can help treat peritoneal metastasis in many advanced gynecologic and gastrointestinal cancers and has shown particular promise in treating advanced ovarian cancer. It is however tremendously underutilized because it requires a lot of resources and the current technology and maximum tolerated dose regimen cause complications and severe toxicity to patients. We previously showed that continuous low-dose IP cisplatin delivery via an implanted diffusion-based reservoir device can be as effective as and less toxic than intermittent maximum tolerated dose IP injections. To translate this work to a clinically relevant implantable system, we developed composite materials that can deliver cisplatin at a continuous low dose that is tunable. The materials were mechanically well suited for placement in the abdomen and were evaluated for in vitro bioactivity, in vivo tolerability and in vivo ability to deliver platinum to key abdominal organs with promising results. Dosing studies with different material dimensions helped identify a dose to pilot treatment of ovarian cancer in human xenograft-bearing mice. The implications of more accessible and affordable IP chemotherapy are especially important in countries with limited resources. Design reviews and a clinician survey in India reveal eagerness for early adoption of new technologies and dosing regimens to treat peritoneal metastasis and show promise for utilization of our implant in the developing world. The work described in this thesis carries implications for the treatment of advanced ovarian cancer and peritoneal metastasis of other tumors affecting millions of patients worldwide and may help with the management of nonmalignant conditions with abdominal involvement.