Drug delivery systems to prevent peritoneal metastasis after surgery of digestives or ovarian carcinoma: A review.

Peritoneum represents a frequent site of metastasis especially for digestive and ovarian primary cancers. The conventional approach to treat peritoneal metastasis consists in systemic chemotherapy, but the median survival associated is only a few months. Recent therapeutic developments result in an aggressive strategy associating cytoreductive surgery (CRS) and hyperthermic intra peritoneal chemotherapy (HIPEC). However, a recent study failed to show an improvement in the overall survival and relapse free survival of this combo in comparison to CRS alone. Confronted to a lack of guidelines, several drug delivery systems (DDS) had been developed and tested in animal models to offer an effective easy-to-use solution for surgeons to prevent peritoneal metastasis. In this work, we reviewed most of the strategies used to treat peritoneal metastasis (PM) from digestive or ovarian origin and concentrated on 3 different DDS strategies: particulates DDS, non particulates DDS (including implants, films and gels) and combination of both (in particular hydrogels loaded with particles).

Combination of tumor cell anti-adhesion and anti-tumor effect to prevent recurrence after cytoreductive surgery in a mice model.

One of the main problems of colorectal cancer is not the treatment of the primary tumor but the metastatic stage. Means of metastatic spread is the invasion of the peritoneal cavity which leads to peritoneal metastasis (PM). PM cannot be easily cured, and the current treatments is rather heavy, combining cytoreductive surgery with intravenous and intraperitoneal chemotherapy. This therapeutic procedure is associated with significant morbidity, altered patient quality of life and poor prognosis. We postulated that development of a prophylactic treatment could be of high interest in this context. In this study, we formulated an anti-adhesive thermogel which contains chemotherapeutics to play a role of a barrier against tumor cells implantation, avoiding their adhesion and treating the remaining tumor cells with chemotherapy intraperitoneally in a mice model of PM. The bioavailability of the thermogel was tested intraperitoneally in mice. No sign of toxicity was observed in terms of change in body weight, anatomopathology and blood biomarkers. In vitro experiments proved that the thermogel induced limited adhesion of the tumor cells. Loading of oxaliplatin (Ox) and 5-Fluorouracil (5-FU) into the thermogel were able to significantly decreased peritoneal carcinomatosis index (PCI) (-58%) and ascites (-70%) in a murine model of peritoneal metastases. These pre-clinical results confirmed that smart thermogel associated with standard chemotherapy 5-FU and Ox could be a good candidate to decrease the risk of tumor cell implantation during cytoreductive surgery and prevent future metastatic process.

Tumour spheres with inverted polarity drive the formation of peritoneal metastases in patients with hypermethylated colorectal carcinomas.

Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-ß signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.