Folate-Targeted Surface-Enhanced Resonance Raman Scattering Nanoprobe Ratiometry for Detection of Microscopic Ovarian Cancer.

Abstract

Ovarian cancer has a unique pattern of metastatic spread, in that it initially spreads locally within the peritoneal cavity. This is in contrast to most other cancer types, which metastasize early on via the bloodstream to distant sites. This unique behavior opens up an opportunity for local application of both therapeutic and imaging agents. Upon initial diagnosis, 75% of patients already present with diffuse peritoneal spread involving abdominal organs. Complete resection of all tumor implants has been shown to be a major factor for improved survival. Unfortunately, it is currently not possible for surgeons to visualize microscopic implants, impeding their removal and leading to tumor recurrences and poor outcomes in most patients. Thus, there is a great need for new intraoperative imaging techniques that can overcome this hurdle. We devised a method that employs folate receptor (FR)-targeted surface-enhanced resonance Raman scattering (SERRS) nanoparticles (NPs), as folate receptors are typically overexpressed in ovarian cancer. We report a robust ratiometric imaging approach using anti-FR-SERRS-NPs (αFR-NPs) and nontargeted SERRS-NPs (nt-NPs) multiplexing. We term this method "topically applied surface-enhanced resonance Raman ratiometric spectroscopy" (TAS3RS ("tasers") for short). TAS3RS successfully enabled the detection of tumor lesions in a murine model of human ovarian adenocarcinoma regardless of their size or localization. Tumors as small as 370 μm were detected, as confirmed by bioluminescence imaging and histological staining. TAS3RS holds promise for intraoperative detection of microscopic residual tumors and could reduce recurrence rates in ovarian cancer and other diseases with peritoneal spread.