siRNA in ovarian cancer - Delivery strategies and targets for therapy

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, and the sixth leading cause of cancer related death in women overall. Despite improved surgical techniques and advances in chemotherapy, mortality hardly decreased over the last twenty years. The major problem is that (micro)metastases persevere in the abdominal cavity, causing incurable tumor recurrence. Therefore, there is an imminent need for new therapeutic strategies. Oligonucleotide (ON) based therapies such as RNA interference (RNAi) provide the possibility to specifically address disease-related pathways. However, small interfering RNA (siRNA) molecules are unable to enter cells without a drug delivery system. Therefore, nanocarriers have been developed to aid intracellular delivery of siRNA. EOC is, in most cases, confined to the abdominal cavity, providing the possibility for peritoneal drug delivery. As a consequence, EOC should be an ideal candidate for ON therapies as intraperitoneal delivery reduces sequestration of drug formulations in other organs. In this review, we will discuss delivery strategies and siRNA targets that have been tested in EOC. Delivery strategies cover the full range of delivery approaches from polymers to exotic delivery strategies like microbubble based nanoparticles. For siRNA targets, those that aim at re-sensitizing the tumor cells to chemotherapy can be discriminated from those that reduce growth and metastasis of the tumor cells. Despite preclinical successes and the advantage that intraperitoneal delivery holds over systemic delivery, no strategy has made it into the clinic yet. We postulate that confirmatory studies that combine the most promising delivery approaches with the most promising targets are required to reach a consensus on those formulations that should be pursued for further (pre-)clinical research.

Keywords: Drug delivery; Gynecologic oncology; Nanomedicine; Ovarian cancer; RNA interference; siRNA.