Rational design of a self-assembling high performance organic nanofluorophore for intraoperative NIR-II image-guided tumor resection of oral cancer

The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 15-26%. Advanced real-time imaging methods that improve detection of tumor margins can help improve success rates. Fluorescence imaging in the second near-infrared (NIR-II) window has the potential to revolutionize the field due to its superior imaging qualities, but NIR-II dyes with adequate in vivo performance and safety profiles are scarce. We report a novel high-performance organic molecule NIR-II fluorophore, XW-03-66 , with a fluorescence quantum yield (QY) of 6.0% in aqueous media. XW-03-66 self-assembles into nanoparticles (~80 nm) and has a systemic circulation half-life (t 1/2 ) of 11.3 h. In mouse models of HPV+ and HPV- OSCC, XW-03-66 outperformed indocyanine green (ICG), a clinically available NIR dye, and enabled intraoperative NIR-II image-guided resection of the tumor and adjacent draining lymph node with negative margins. In vitro and in vivo toxicity assessments revealed minimal safety concerns for in vivo applications.