Tumor Receptor-Seeking Dyes for Rapid Intraoperative Definition of Tumor Margin and Histopathological Morphology

Abstract

Histopathological diagnosis is a crucial part of surgical treatment, as it determines further treatment decisions and prognosis for patients. Due to the heterogeneity of tumors, traditional histopathological diagnosis relies on histological and cytological morphological analysis of cryo-slides by well-trained pathologists, which is subjective, time-consuming, and lacks considerable reliability. Therefore, we engineer a series of tumor receptor-seeking dyes to automatically label and visually depict the tumor contour with antibody-free interaction. The meso-chlorine on the cyclohexyl ring of dyes can covalently react with specific thiol groups in various tumor signature proteins to form stable dye@protein complexes. These dye@protein complexes have significantly amplified fluorescence signals in tumor sites, enabling high-resolution delineation of tumor margins and providing histological morphology information to potentially determine tumor staging. The orthogonal effect not only avoids errors caused by individual signature proteins, but also amplifies the fluorescence difference between tumor and normal tissues. Notably, our method is easy to operate with a minimal detection time of only 4 min. The tumor receptor-seeking dyes successfully assess tumor-positive margins from 66 resected breast tumor samples and 25 intraoperative cancer patients with 100% accuracy, providing a new-generation technique for intraoperative pathologic diagnosis of tumor biopsy.