One major issue during cytoreductive surgeries in the treatment of peritoneal carcinomatosis is to detect tumor cells scattering in early stages of the pathology as well as after the surgery. Imaging tools currently available are not specific and unable to properly assist clinicians to assure completeness of the cytoreduction and avoid relapses. IPBS researchers developed a protein nanoprobe enabling fluorescence detection of submillimeter nodules, in a size range 20 times lower than what can be seen to the naked eye. This work has been published in Biomaterials on February 22, 2020.
The development of targeted therapy and imaging tools is a major challenge in human health, particularly in cancer pathologies. Peritoneal carcinomatosis is usually caused by scattering of cancer cells within the abdominal cavity, which is the case for 85% of ovarian cancer patients and more than 10% of colorectal cancer patients. In both cases treatments include a cytoreductive surgery, as complete as possible, and chemotherapies. Patients overall survival improvement can be reach with the development of parallel technologies such as new diagnostic tools to detect early implantations in the peritoneal cavity, combined chemotherapies and intraperitoneal targeted treatments.
In order to improve this detection, the researchers targeted a modified glycosylation, carried by different membrane glycoproteins and specific of epithelial tumor cells, the Thomsen-Friedenreich antigen (TF) or CD176. The probe is a protein, belonging to the lectins family, that specifically recognize this aberrant glycosylation. Mice were xenograft with ovarian tumor cells directly injected into the abdominal cavity. The graft protocol has been developed to obtain submillimeter nodules (<mm3), corresponding to the current detection limit in surgery, and those nodules were implanted on identical sites as the one observed in human pathology. The protein has been labelled with a near infrared fluorescent dye, and then intraperitoneally injected in mice. In order to mimic two clinical situations, the probe has been injected at two different times. On one hand, 3 weeks after tumor cells xenograft to detect nodules corresponding to an already established relapse. On the other hand, the probe has been injected at the same time as tumor cells engraftment. This second situation is equivalent to what happens right after cytoreductive surgery when cancer cells are able to disseminate in the abdominal cavity, re-implant and lead to relapses during several months to years’ period (iatrogenic effect). This protocol allowed the researchers to prove that it was possible to detect these scattering tumor cells during more than 3 weeks.
The researchers demonstrated last year that this protein also enabled to transport small chemotherapeutic molecules directly to tumor cells (Nanoscale, 2019, 11, 3248 – 3260). The combination of those two properties paves the way for theranostic approaches in which therapy and imaging diagnostic are coupled and realized with a single nano-object.
The protein has been labelled in near infrared (Alexa 647) et intraperitoneally injected in ovarian tumor-bearing mice. Very small nodules have been detected (top right panel). The detection limit is around 20 times higher compared to current available systems. The nodules have been sampled and analyzed in confocal microscopy (right bottom panel). Green : tumor cells ; red : fluorescent probe.
This work was conducted in collaboration with the ICR-IUCT Oncopole and the Urosphere company.
Development of a near infrared protein nanoprobe targeting Thomsen-Friedenreich antigen for intraoperative detection of submillimeter nodules in an ovarian peritoneal carcinomatosis mouse model
Mathilde Coustets, Caroline Ladurantie, Elisabeth Bellard, Mélissa Prat, Marie-Pierre Rols, Vincent Ecochard, Gwenaël Ferron, Sophie Chabot, Muriel Golzio, Laurent Paquereau. Biomaterials. 2020 241:119908. DOI: 10.1016/j.biomaterials.2020.119908
Researcher IPBS: Laurent Paquereau | Laurent.Paquereau@ipbs.fr | 05 61 17 58 59
Press IPBS: Francoise Viala | Communication@ipbs.fr | 06 01 26 52 59