Highly Specific and Sensitive Fluorescent Nanoprobes for Image-Guided Resection of Sub-Millimeter Peritoneal Tumors

A current challenge in the treatment of peritoneal carcinomatosis is the inability to detect, visualize, and resect small or microscopic tumors of pancreatic, ovarian, or mesothelial origin. In these diseases, the completeness of primary tumor resection is directly correlated with patient survival, and hence, identifying small sub-millimeter tumors (i.e., disseminated disease) is critical. Thus, new imaging techniques and probes are needed to improve cytoreductive surgery and patient outcomes. Highly fluorescent rhodamine-labeled expansile nanoparticles (HFR-eNPs) are described for use as a visual aid during cytoreductive surgery of pancreatic carcinomatosis. The covalent incorporation of rhodamine into ∼30 nm eNPs increases the fluorescent signal compared to free rhodamine, thereby affording a brighter and more effective probe than would be achieved by a single rhodamine molecule. Using the intraperitoneal route of administration, HFR-eNPs localize to regions of large (∼1 cm), sub-centimeter, and sub-millimeter intraperitoneal tumor in three different animal models, including pancreatic, mesothelioma, and ovarian carcinoma. Tumoral localization of the HFR-eNPs depends on both the material property (i.e., eNP polymer) as well as the surface chemistry (anionic surfactant vs PEGylated noncharged surfactant). In a rat model of pancreatic carcinomatosis, HFR-eNP identification of tumor is validated against gold-standard histopathological analysis to reveal that HFR-eNPs possess high specificity (99%) and sensitivity (92%) for tumors, in particular, sub-centimeter and microscopic sub-millimeter tumors, with an overall accuracy of 95%. Finally, as a proof-of-concept, HFR-eNPs are used to guide the resection of pancreatic tumors in a rat model of peritoneal carcinomatosis.